Francisella tularensis is considered a Category A agent by the NIAID because of its extreme infectivity, ease of dissemination, and substantial capacity to cause illness and death. The "characterization of innate and adaptive immune responses that occur after initial exposure to F. tularensis" has been identified as one of the priorities of NIAID's Counter-Bioterrorism Research Agenda. The pneumonic form of tularemia is the deadliest form of disease and the form most likely to be used by bioterrorists, yet the great majority of research against this organism has focused on systemic infection rather than pulmonary tularemia. The overriding hypothesis of the Program Project is that the pathogenesis of F. tularensis in the respiratory tract is unique and that distinct mechanisms of mucosal-specific immunity are required for protection against pneumonic tularemia. The Program Project brings together a diverse group of individuals with particular expertise in the fields of microbiology, cell biology, and mucosal immunology who will explore in an integrated fashion, the immune response to F. tularensis. The four subprojects will: 1) Define the immunobiology of F. tularensis-macrophage interactions and determine the influence of macrophage activation state on killing of the organism, antigen presentation, and elaboration of inflammatory cytokines. 2) Examine the role of F. tularensis pattern recognition by the innate immune system in fostering lung inflammation. 3) Determine the importance of mucosal immune mechanisms in protection against pneumonic tularemia and develop novel strategies for induction of protective respiratory immunity. 4) Develop F. tularensis mutants to investigate the pathogenic consequences of the organism's interactions with macrophages. The overall goal of the Project is to characterize the association of F. tularensis with macrophages, particularly alveolar macrophages, and develop approaches for effective protection at mucosal surfaces. The results of these studies will ultimately be used to evaluate new mucosal vaccination strategies and new vaccine candidates against human respiratory infection with F. tularensis.